Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl-terminal sequence. In addition to SP the known mammalian tachykinins include neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively.
Evidence has been reviewed for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Chrohn""s disease, ocular injury and ocular inflammatory diseases, proliferative vitreoretinopathy, irritable bowel syndrome and disorders of bladder function including cystitis and bladder detruser hyperreflexia.
It has furthermore been suggested that tachykinin receptor antagonists have utility in the following disorders: anxiety, depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld""s disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorder related to immune enhancement or suppression such as systemic lupus erythmatosus, ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Attempts have been made to provide antagonists for the receptors of substance P and other tachykinin peptides in order to more effectively treat the various disorders and diseases mentioned above. For example, U.S. Pat. Nos. 5,387,595, 5,750,549 and Bioorg. and Med. Chem. Lett., 1345 (1995) disclose certain alicyclic compounds as tachykinin receptor antagonists.
This invention is concerned with novel compounds represented by structural formula I: 
or a pharmaceutically acceptable salt thereof, wherein R3, R5, R6, R7, R8, R11, R12, R13, Q, W, X, Y and Z are defined herein. The invention is also concerned with pharmaceutical formulations comprising these novel compounds as active ingredients and the use of the novel compounds and their formulations in the treatment of certain disorders. The compounds of this invention are tachykinin receptor antagonists and are useful in the treatment of psychiatric disorders including depression and anxiety.
The present invention is directed to compounds of the structural formula I: 
or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl,
(3) C1-6 alkyl-OH, and
(4) C1-6 alkyl-Oxe2x80x94C1-6 alkyl;
W is selected from the group consisting of:
(2) xe2x80x94NHxe2x80x94, and
(3) xe2x80x94N(C1-6 alkyl)-;
X is selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl, and
(3) C1-6 alkyl-OH;
Y is selected from the group consisting of:
(1) a single bond, and
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo, wherein halo is fluoro, chloro, bromo or iodo,
(h) xe2x80x94NR9R10, wherein R9 and R10 are independently selected from:
(I) hydrogen,
(II) C1-6 alkyl,
(III) phenyl,
(IV) (C1-6 alkyl)-phenyl,
(V) (C1-6 alkyl)-hydroxy, and
(VI) (C1-6 alkyl)-(C1-4 alkoxy),
(i) xe2x80x94NR9xe2x80x94COR10,
(j) xe2x80x94NR9xe2x80x94CO2R10,
(k) xe2x80x94COxe2x80x94NR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
Z is selected from the group consisting of:
C1-6 alkyl,C3-6 cycloalkyl and C1-6 alkyl(C3-6 cycloalkyl), which is unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9xe2x80x94COR10,
(j) xe2x80x94NR9xe2x80x94CO2R10,
(k) xe2x80x94COxe2x80x94NR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9;
R3 is selected from the group consisting of:
(1) xe2x80x94CO2H,
(2) -tetrazolyl, and
(3) xe2x80x94COxe2x80x94NHxe2x80x94SO2xe2x80x94CH3;
R5 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9xe2x80x94COR10,
(j) xe2x80x94NR9xe2x80x94CO2R10,
(k) xe2x80x94COxe2x80x94NR9R10,
(l) xe2x80x94COR9, and
(m) xe2x80x94CO2R9,
or R5 and Z may be joined together to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring which is substituted with R3 and further substituted with one or more of the substituents selected from:
(a) C1-6 alkyl,
(b) (C1-6 alkyl)-phenyl,
(c) (C1-6 alkyl)-hydroxy,
(d) (C1-6 alkyl)-(C1-4 alkoxy),
(e) hydroxy,
(f) oxo,
(g) C1-6 alkoxy,
(h) phenyl-C1-3 alkoxy,
(i) phenyl,
(j) xe2x80x94CN,
(k) halo,
(l) xe2x80x94NR9R10,
(m) xe2x80x94NR9xe2x80x94COR10,
(n) xe2x80x94NR9xe2x80x94CO2R10,
(o) xe2x80x94COxe2x80x94NR9R10,
(p) xe2x80x94COR9, and
(q) xe2x80x94CO2R9,
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkoxy,
(3) halo,
(4) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9xe2x80x94COR10,
(j) xe2x80x94NR9xe2x80x94CO2R10,
(k) xe2x80x94COxe2x80x94NR9R10,
(l) xe2x80x94COR9,
(m) xe2x80x94CO2R9,
(n) heterocycle, wherein heterocycle is selected from the group consisting of:
(A) benzimidazolyl,
(B) benzofuranyl,
(C) benzothiophenyl,
(D) benzoxazolyl,
(E) furanyl,
(F) imidazolyl,
(G) indolyl,
(H) isooxazolyl,
(I) isothiazolyl,
(J) oxadiazolyl,
(K) oxazolyl,
(L) pyrazinyl,
(M) pyrazolyl,
(N) pyridyl,
(O) pyrimidyl,
(P) pyrrolyl,
(Q) quinolyl,
(R) tetrazolyl,
(S) thiadiazolyl,
(T) thiazolyl,
(U) thienyl,
(V) triazolyl,
(W) azetidinyl,
(X) 1,4-dioxanyl,
(Y) hexahydroazepinyl,
(Z) piperazinyl,
(AA) piperidinyl,
(AB) pyrrolidinyl,
(AC) morpholinyl,
(AC) thiomorpholinyl,
(AD) dihydrobenzimidazolyl,
(AE) dihydrobenzofuranyl,
(AF) dihydrobenzothiophenyl,
(AG) dihydrobenzoxazolyl,
(AH) dihydrofuranyl
(AI) dihydroimidazolyl,
(AJ) dihydroindolyl,
(AK) dihydroisooxazolyl,
(AL) dihydroisothiazolyl,
(AM) dihydrooxadiazolyl,
(AN) dihydrooxazolyl,
(AO) dihydropyrazinyl,
(AP) dihydropyrazolyl,
(AQ) dihydropyridinyl,
(AR) dihydropyrimidinyl,
(AS) dihydropyrrolyl,
(AT) dihydroquinolinyl,
(AU) dihydrotetrazolyl,
(AV) dihydrothiadiazolyl,
(AW) dihydrothiazolyl,
(AX) dihydrothienyl,
(AY) dihydrotriazolyl,
(AZ) dihydroazetidinyl,
(BA) dihydro-1,4-dioxanyl,
(BB) tetrahydrofuranyl, and
(BC) tetrahydrothienyl,
xe2x80x83and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-6 alkyl, unsubstituted or substituted with halo, xe2x80x94CF3xe2x80x94OCH3, or phenyl,
(ii) C1-6 alkoxy,
(iii) oxo,
(iv) hydroxy,
(v) thioxo,
(vi) xe2x80x94SR9,
(vii) halo,
(viii) cyano,
(ix) phenyl,
(x) trifluoromethyl,
(xi) xe2x80x94(CH2)mxe2x80x94NR9R10,
(xii) xe2x80x94NR9COR10,
(xiii) xe2x80x94CONR9R10,
(xiv) xe2x80x94CO2R9, and
(xv) xe2x80x94(CH2)mxe2x80x94OR9,
(5) hydroxy,
(6) xe2x80x94CN,
(7) xe2x80x94CF3,
(8) xe2x80x94NO2,
(9) xe2x80x94SR14, wherein R14 is hydrogen or C1-6alkyl,
(10) xe2x80x94SOR14,
(11) xe2x80x94SO2R14,
(12) xe2x80x94NR9xe2x80x94COR10,
(13) xe2x80x94COxe2x80x94NR9xe2x80x94COR10,
(14) xe2x80x94NR9R10,
(15) xe2x80x94NR9xe2x80x94CO2R10,
(16) xe2x80x94COR9,
(17) xe2x80x94CO2R9,
(18) heterocycle, wherein heterocycle is as defined above,
(19) xe2x80x94(C1-6alkyl)-heterocycle, wherein heterocycle is as defined above,
(20) xe2x80x94N(heterocycle)xe2x80x94SO2R14, wherein heterocycle is as defined above;
R11, R12 and R13 are independently selected from:
(1) hydrogen,
(2) C1-6 alkyl, unsubstituted or substituted with one or more of the substituents selected from:
(a) hydroxy,
(b) oxo,
(c) C1-6 alkoxy,
(d) phenyl-C1-3 alkoxy,
(e) phenyl,
(f) xe2x80x94CN,
(g) halo,
(h) xe2x80x94NR9R10,
(i) xe2x80x94NR9xe2x80x94COR10,
(j) xe2x80x94NR9xe2x80x94CO2R10,
(k) xe2x80x94COxe2x80x94NR9R10,
(l) xe2x80x94COR9,
(m) xe2x80x94CO2R9;
(3) halo,
(4) xe2x80x94CN,
(5) xe2x80x94CF3,
(6) xe2x80x94NO2,
(7) hydroxy,
(8) C1-6alkoxy,
(9) xe2x80x94COR9, and
(10) xe2x80x94CO2R9;
and pharmaceutically acceptable salts and individual diasteromers thereof.
Asymmetric centers may be present in the compounds of the instant invention depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixture and as pure or partially purified compounds are included within the ambit of this invention.
In addition compounds with carbon-carbon double bonds may occur in Z- and E-forms with all isomeric forms of the compounds being included in the present invention.
When any variable (e.g., alkyl, aryl, Q, W, X, Y, Z, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, m, n, etc.) occurs more than one time in any variable or in Formula I, its definition on each ocurrence is independent of its definition at every other occurrence.
As used herein, the term xe2x80x9calkylxe2x80x9d includes those alkyl groups of a designated number of carbon atoms of either a straight, branched, or cyclic configuration. Examples of xe2x80x9calkylxe2x80x9d include methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, butoxy and pentoxy. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of a specified number of carbon atoms of either a straight- or branched-configuration and at least one unsaturation, which may occur at any point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, dimethylpentyl, and the like, and includes E and Z forms, where applicable. xe2x80x9cHalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d, as used herein, means fluoro, chloro, bromo and iodo.
In the compounds of the present invention, if Y is a single bond, then xe2x80x94N(R5)xe2x80x94Zxe2x80x94R3 is attached directly to the cyclopentyl ring.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Suitable salts are found, e.g. in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418.
One embodiment of the present invention is directed to the compounds of structural formula I, or a pharmaceutically acceptable salt thereof, in which W is xe2x80x94Oxe2x80x94 of the formula: 
or a pharmaceutically acceptable salt thereof, wherein R3, R5, R6, R7, R8, R11, R12, R13, Q, W, X, Y and Z are defined herein.
One group within the embodiment of the compounds of the invention where W is xe2x80x94Oxe2x80x94 is that wherein Q is C1-6 alkyl.
One group within the embodiment of the compounds of the invention where W is xe2x80x94Oxe2x80x94 is that wherein Q is C1-6 alkyl-OH.
One group within the embodiment of the compounds of the invention where W is xe2x80x94Oxe2x80x94 is that wherein Q is hydrogen.
In the compounds of the present invention where W is xe2x80x94Oxe2x80x94, it is preferred that Q is hydrogen, xe2x80x94CH3 or xe2x80x94CH2xe2x80x94OH.
An embodiment of the present invention includes those compounds of structural formula I, or a pharmaceutically acceptable salt thereof, wherein:
Q is selected from the group consisting of:
(1) hydrogen,
(2) xe2x80x94CH3, and
(3) xe2x80x94CH2xe2x80x94OH;
W is xe2x80x94Oxe2x80x94;
X is hydrogen;
Y is selected from the group consisting of:
(1) a single bond,
(2) xe2x80x94CH2xe2x80x94, and
(3) xe2x80x94CH2xe2x80x94OH;
Z is selected from the group consisting of: C1-6 alkyl,C3-6 cycloalkyl and C1-6 alkyl(C3-6 cycloalkyl);
R3 is xe2x80x94CO2H;
R5 is selected from the group consisting of:
(1) hydrogen, and
(2) C1-6 alkyl,
or R5 and Z are joined together to form a piperidinyl ring which is substituted with R3 and which is further unsubstituted or substituted with C1-6 alkyl;
R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) xe2x80x94CF3,
(3) C1-6alkoxy, and
(4) 1-, 2- or 5-tetrazolyl, wherein the tetrazolyl is unsubstituted or substituted with a substitutent selected from the group consisting of:
(a) C1-6 alkyl,
(b) -cyclopropyl,
(c) CH2-cyclopropyl,
(d) xe2x80x94Sxe2x80x94C1-4alkyl,
(e) xe2x80x94SOxe2x80x94C1-4alkyl,
(f)
SO2xe2x80x94C1-4alkyl,
(g) phenyl,
(h) xe2x80x94NR9R10,
(i) xe2x80x94CH2xe2x80x94COxe2x80x94CF3, and
(j) xe2x80x94CF3;
R11, R12 and R13 are independently selected from:
(1) hydrogen, and
(2) fluoro;
and pharmaceutically acceptable salts and individual diasteromers thereof.
An embodiment of the present invention includes those compounds wherein Q is selected from the group consisting of:
(1) hydrogen,
(2) xe2x80x94CH3, and
(3) xe2x80x94CH2xe2x80x94OH.
An embodiment of the present invention includes those compounds wherein Q is xe2x80x94CH3.
An embodiment of the present invention includes those compounds wherein W is xe2x80x94Oxe2x80x94.
An embodiment of the present invention includes those compounds wherein Y is selected from the group consisting of:
(1) a single bond,
(2) xe2x80x94CH2xe2x80x94, and
(3) xe2x80x94CH2xe2x80x94OH.
An embodiment of the present invention includes those compounds wherein Y is xe2x80x94CH2xe2x80x94.
An embodiment of the present invention includes those compounds wherein R3 is xe2x80x94CO2H.
An embodiment of the present invention includes those compounds wherein R5 is selected from the group consisting of:
(1) hydrogen, and
(2) methyl.
An embodiment of the present invention includes those compounds wherein Z is selected from the group consisting of:
(1) xe2x80x94CH2xe2x80x94,
(2) xe2x80x94CH2CH2xe2x80x94,
(3) xe2x80x94CH2C(CH3)2xe2x80x94,
(4) xe2x80x94CH2C(CH2CH3)2xe2x80x94,
(5) xe2x80x94CH2C(CH3)(CH(CH3)2)xe2x80x94,
(6) xe2x80x94CH2C(cyclopentyl)-, and
(7) xe2x80x94CH2C(cyclohexyl)-.
An embodiment of the present invention includes those compounds wherein R5 and Z are joined together to form a piperidinyl ring which is substituted with R3 and which is further unsubstituted or substituted with methyl.
An embodiment of the present invention includes those compounds wherein R6, R7 and R8 are independently selected from the group consisting of:
(1) hydrogen,
(2) xe2x80x94CF3,
(3) C1-4alkoxy, and
(4) heterocycle, wherein the heterocycle is selected from the group consisting of:
(A) tetrazolyl,
(B) imidazolyl,
(C) triazolyl,
(D) pyridyl,
and wherein the heterocycle is unsubstituted or substituted with one or more substituent(s) selected from:
(i) C1-4 alkyl,
(ii) -cyclopropyl, and
(iii) xe2x80x94CF3.
An embodiment of the present invention includes those compounds wherein the phenyl ring bearing R6, R7 and R8 is selected from:
3,5-bis(trifluormethyl)phenyl,
2-methoxy-5-tetrazol-1-yl-phenyl,
2-methoxy-5-(5-methyl-tetrazol-1-yl)-phenyl,
2-methoxy-5-(5-ethyl-tetrazol-1-yl)-phenyl,
2-methoxy-5-(5-propyl-tetrazol-1-yl)-phenyl,
2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-phenyl,
2-methoxy-5-(5-cyclopropyl-tetrazol-1-yl)-phenyl, and
2-methoxy-5-(5-methylsulfanyl-tetrazol-1-yl)-phenyl.
An embodiment of the present invention includes those compounds wherein R11, R12 and R13 are independently selected from:
(1) hydrogen, and
(2) fluoro.
An embodiment of the present invention includes those compounds wherein the phenyl ring bearing R11, R12 and R13 is unsubstituted phenyl or is parafluorophenyl.
Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.
Specific compounds within the present invention include a compound which selected from the group consisting of the title compounds of the Examples; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
Specific compounds within the present invention include:
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R and/or S)-3-carboxylpyrrolidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((2-carboxylethyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-((2-carboxylethyl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-((3-carboxylpropyl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((3-carboxylpropyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxyl-4-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-((carboxylmethyl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-2-carboxylpyrrolidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((RS)-3-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((3-carboxylazetidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((2-carboxylethyl)amino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((carboxylmethyl)amino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((S)-1-carboxylethyl)amino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((R)-1-carboxylethyl)amino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(ethylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-(tetrazol-5-yl)piperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((2-(tetrazol-5-yl)ethyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(S)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3-Fluoro-5-trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-(methylsulfonylaminocarbonyl)piperidin-1-yl) methyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(carboxyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(hydroxymethyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-2-carboxylpyrrolidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R,S)-3-carboxylpyrrolidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((2-carboxylethyl)amino)methyl)cyclopentane;
1-(S)-(1-(3,5-Bis(trifluoromethyl)phenyl)methoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((2-carboxylethyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(hydroxymethyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((2-carboxylethyl)methyl)amino)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R,S)-3-carboxylpyrrolidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((4-carboxyl-4-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R and S)-3-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-3-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((RS)-3-carboxylpiperazin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((RS)-2- carboxyl-1-methylpiperazin-4-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((RS)-2-carboxylmorpholin-4-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-3-carboxyl-3-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-3-carboxyl-3-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-2-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-2-carboxylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((1-carboxyl-1-methyl)ethyl)aminomethyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((R)-1-carboxyl-1,2-dimethylprop-1-yl)amino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((S)-1-carboxyl-1,2-dimethylprop-1-yl)aminomethyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-3-carboxyl-(R)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-3-carboxyl-(R)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-3-carboxyl-(S)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-2-carboxyl-(R)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-2-carboxyl-(S)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-2-carboxyl-(R)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-2-carboxyl-(S)-5-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((S)-1-carboxylethyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((R)-1-carboxylethyl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((((RS)-2-carboxylprop-1-yl)methylamino)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-3-carboxyl-3-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(S)-(3,5-Bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((S)-3-carboxyl-3-methylpiperidin-1-yl)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-((2-carboxyl-2-methylprop-1-yl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-((2-carboxyl-2-ethylbut-1-yl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((1-carboxylcyclopent-1-yl)methyl)methylamino)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((1-carboxylcyclohex-1-ylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((1-carboxylcyclopent-1-ylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((1-carboxylcyclohex-1-yl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((1-carboxylcyclopent-1-yl)methylamino)methyl)cyclopentane;
1-(S)-(1-(R)-(3,5-Bis(trifluoromethyl)phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-(((R)-3-carboxylpiperidin-1-yl)methyl)cyclopentane;
and pharmaceutically acceptable salts and individual diasteromers thereof.
There are several acceptable methods of naming the compounds discussed herein. 
For example, the racemic mixture of A and B shown above can be named either as xe2x80x9c(1RS,2RS,3RS)-2-(4-fluorophenyl)-3-hydroxycyclopentane-carboxylic acid methyl esterxe2x80x9d or as xe2x80x9cmethyl 3-(SR)-hydroxy-2-(SR)-(4-fluoro)phenyl-1-(SR)-carboxylatexe2x80x9d.
Throughout the instant application, the following abbreviations are used with the following meanings:
The preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the following reaction schemes. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures includes crystallization, normal phase or reverse phase chromatography.
Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples wherein the variables are as defined above or as defined herein. 
Intermediates for preparation of the compounds of the present invention in which the central ring is 5-membered may be synthesized by the general route outlined in Scheme 1. Thus, according to the procedure of Baker and Leeds (J. Chem. Soc 1948, 974), condensation of ethyl cyanoacetate and benzaldehyde (with or without substituents) in the presence of a base such as piperidine provides the unsaturated derivative I. Exposure of this olefin to sodium cyanide followed by ethyl 3-chloropropionate gives the dicyano derivative II which after aqueous acidic hydrolysis yields triacid III. After esterification with acidic methanol, the triester may be cyclized by heating with sodium methoxide in dry methanol followed by treatment with aqueous hydrochloric acid, to provide racemic cyclopentanone IV. The methyl ester V may be formed from ketone IV by treatment with acidic methanol or diazomethane in ether. 
The reduction of ester V may be accomplished with various reducing agents, for example, sodium borohydride, lithium aluminum hydride, di-isobutyl aluminum hydride, lithium tri(sec-butyl)-borohydride and the like, or with hydrogen in the presence of a suitable catalyst, such as platinum oxide or 5% palladium on carbon, which provide the corresponding cis- and trans- alcohols VI and VII, respectively (Scheme 2). The ratio of VI to VII thus obtained is dependent on the reducing agent employed. Alcohols VI and VII may be interconverted by oxidation to ketone V with chromium trioxide, pyridinium chlorochromate, DMSO/oxalyl chloride/triethylamine or similar agents followed by reduction with one of the reagents given above. Separation of the enantiomers of esters VI and VII may be carried out by hydrolysis to the corresponding acids VII and IX followed by fractional crystallization of the salts formed with R-(+)- or S-(xe2x88x92)-xcex1-methylbenzylamine or other suitable chiral, non-racemic bases. 
An alternative method of resolution is shown in Scheme 3. The racemic acid (+/xe2x88x92)-IV is activated with, for example, oxalyl chloride, DCC, EDAC/HOBt or similar condensing reagents, and then allowed to react with a chiral, non-racemic alcohol, such as (S)-alpha-methylbenzyl alcohol, to give the esters X and XI. After separating these diastereomers, they are individually treated with a suitable reducing agent, such as sodium borohydride, to give mixtures of the corresponding alcohols, which are then transesterified with methanol to provide the separate enantiomers of esters VI and VII. 
Conversion of the free acids to the methyl esters is accomplished as shown in Scheme 4. Interconversion of the non-racemic cis and trans alcohols VI and VII may be carried out by oxidation to the non-racemic ketone V followed by reduction with an appropriate reducing agent as given above. 
As shown in Scheme 5, O-alkylation of alcohols VI and VII may be carried out by several procedures, for example, treatment with sodium hydride followed by addition of a benzylic halide, alkylsulfonate or arylsulfonate; exposure of VI or VI to a benzylic trichloroacetimidate in the presence of a strong acid such as trifluoromethanesulfonic acid; or treatment with a benzylic trifluoromethanesulfonic ester, to give ether XII. 
Ester XII may be reduced with a hydride-reducing agent such as lithium aluminum hydride, lithium borohydride or di-isobutylaluminum hydride to provide the primary alcohol XIII, which may be further functionalized by standard acylation or etherification, reactions (Scheme 6). Alternatively, the hydroxyl group may be replaced by a leaving group such as a bromide (by exposure to triphenylphosphine-bromine or triphenylphosphine-carbon tetrabromide), an iodide (by treatment with methanesulfonyl chloride followed by sodium iodide) or a p-toluenesulfonate (by treatment with p-TsCl in the presence of a suitable base such as pyridine). The leaving group may then be displaced by a variety of nucleophiles such as unsubstituted, mono- or disubstituted amines R9(R10)NH, to give amine XIV. 
Alternatively, as shown in Scheme 7 the leaving group may be displaced by azide anion and the azide group reduced by treatment with either triphenylphosphine/water or hydrogenation in the presence of a suitable metal catalyst to give the primary amine XV. 
Primary amine XV may also be prepared by the route shown in Scheme 8. Hydrolysis of ester XII to the acid XVI, followed by formation of the acid chloride and exposure to aqueous ammonia, provides primary amide XVII. Reduction with borane-methyl sulfide, lithium aluminum hydride, or a similar reagent then gives amine XV. 
Treatment of acid XVI with oxalyl chloride and then sodium azide provides the corresponding acyl azide, which upon thermolysis provides isocyanate XVIII (Scheme 9). Treatment of XVIII with an alcohol R9OH gives the carbamate XIX, while reaction of XVIII with an amine R9(R10)NH provides the urea XX. 
In the specific case where R9OH=PhCH2OH, the CBZ-protected amine XXI is obtained, which may be de-protected under standard conditions (for example, H2, 10% Pd/C) to afford primary amine XXII (Scheme 10). 
If the enantiomers have not been separated up to this point, the isocyanate may be treated with a chiral, non-racemic alcohol such as (R)-(+)-alpha-methylbenzyl alcohol to form diastereomeric carbamates XXIII, which after diastereomer separation by, for example, fractional crystallization or chromatography, may be converted to the non-racemic primary amine XXII by reduction or hydrolysis (Scheme 11). 
Alkylation of carbamate XXIV may be carried out by treatment with a suitable base such as sodium hydride followed by addition of an alkylating agent R9X, where Xxe2x95x90Cl, Br, I, OMs, or OTs, to afford XXV (Scheme 12). Cleavage of the carbamate under conditions described previously gives secondary amine XXVI. 
Alkylation of amines XXII, XXVI, XV or XIV may be carried out by treatment with a number of reagents, such as t-butyl or benzyl bromoacetate or chloropropanoate (Scheme 13). The t-butyl esters XXVII (R=t-Bu) may be cleaved by exposure to trifluoroacetic acid to provide the carboxylic acid XXVII, while esters XXVII (R=Bn) may be converted to the acids XXVIII by hydrogenolysis and esters XXVII (R=Me or Et) may be converted to the acids XXVIII by basic hydrolysis. 
Alkylation of amine XXII or amine XXVI may also be carried out by reductive amination with an appropriate aldehyde in the presence of a reducing agents such as sodium triacetoxyborohydride in DCE or sodium cyanoborohydride in methanol (Scheme 14). The reductive amination can also be done catalytically with 10% palladium on carbon in methanol. The t-butyl esters XXIX (R=t-Bu) may be cleaved by exposure to trifluoroacetic acid to provide the carboxylic acid XXX, while esters XXIX (R=Bn) may be converted to the acids XXX by hydrogenolysis. 
Oxidation of alcohol XIII (Scheme 6) to aldehyde XXXI can be accomplished with oxalyl chloride/DMSO/DIPEA in methylene chloride (Swern oxidation) or similar oxidation routes which stop at the aldehyde oxidation state (Scheme 15). Reductive amination of primary or secondary amines with XXXI to afford amino-esters XXXII can be carried out in the presence of reducing agents such as sodium triacetoxyborohydride in DCE or sodium cyanoborohydride in methanol. The reductive amination can also be done catalytically with 10% palladium on carbon in methanol. The esters XXXII may be cleaved to the corresponding acids XXXIII as previously described depending on R. 
Reductive amination of cyclic amines with XXXI to afford amino-esters XXXIV can be carried in the presence of a reducing agents such as sodium triacetoxyborohydride in DCE or sodium cyanoborohydride in methanol (Scheme 17). The esters XXXII may be cleaved to the corresponding acids XXXV as previously described depending on R. 
Benzylamine derivatives may be prepared as shown in Scheme 18. Treatment of ketone X with 4-methoxybenzylamine in the presence of a suitable reducing agent such as sodium cyanoborohydride provides a mixture of the cis and trans amines XXXIX and XL. Alkylation with a benzyl halide, benzyl alkylsulfonate or benzyl arylsulfonate followed by acidic methanolysis and then hydrogenolysis with 10% Pd/C provides the N-benzylated derivatives XLI and XLII. 
An alternative method for the synthesis of a 3-amino derivative is shown in Scheme 21. Treatment of hydroxy esters VI or VII with an activating agent, such as p-toluenesulfonyl chloride, methanesulfonyl chloride, trifluoromethane sulfonic anhydride, or similar agents, followed by treatment with sodium azide in DMF, provides the azide XLIX or L, respectively, in which the stereochemistry of the starting hydroxyl group has been inverted. Alternatively, activation of the alcohol VI or VII with a halogenating agent, for example triphenylphosphine/carbon tetrabromide or triphenylphosphine dibromide, followed by displacement with azide, results in formation of azides XLIX or L with overall retention of hydroxyl stereochemistry. Another method to produce the azide with inversion of stereochemistry involves treating the alcohol with triphenylphosphine, diethyl azodicarboxylate and zinc azide bis(pyridine) complex, in the presence of 2 equivalents of imidazole. 
The azides XLIX and L can be converted directly to the primary amines LI and LII by either catalytic reduction, for example, with hydrogen and 10% Pd/C in methanol, or by treatment with a trialkyl- or triaryl- phosphine, followed by hydrolysis (Scheme 22). Alternatively, azides XLIX and L can be treated with trimethylphosphine in THF in the presence of 4 A molecular sieves followed by direct addition of an aryl or heteroaryl aldehyde, to produce the intermediate imine. This can be reduced by taking up the imine in methanol and adding sodium cyanoborohydride, sodium tris(acetoxy)borohydride, or sodium borohydride in the presence of acetic acid, or by hydrogenating in the presence of a palladium on carbon catalyst, to provide the secondary amine LIII and LIV, respectively. 
Preparation of derivatives wherein an alkyl chain Q is present at the benzylic position are prepared according to the procedure in Scheme 23. Addition of an alkyl magnesium halide or alkyllithium reagent to the aldehyde intermediate LXXXIX provides secondary alcohol XC. Conversion of the hydroxyl group to a leaving group, for example by formation of the tosylate, mesylate, triflate, bromide or iodide produces an intermediate XCl (when the leaving group is bromide) that can be used to alkylate amines LI and LII in refluxing acetonitrile in the presence of a suitable hindered amine base, such as DIEA, to give XCII and XCIII, respectively. 
Preparation of intermediates which lead to analogs where Y is a methylene group, Z is absent and R3 is an N-alkyl tetrazo-5-yl group is shown in Scheme 24. Protection of the hydroxyl group of ester CXXI followed by basic hydrolysis gives benzyl ether CXXXII. Reduction with lithium aluminum hydride and then treatment with triphenylphosphine and carbon tetrabromide affords bromide CXXXIII. Displacement with sodium cyanide and then treatment with sodium azide in the presence of ammonium chloride in DMF provides tetrazole CXXXIV. Alkylation under basic conditions provides a mixture of 1-alkyl- and 2-alkyl tetrazoles CXXXV, which can be converted to the desired azide intermediates by hydrogenolytic deprotection and then by treatment with zinc diazide bis(pyridine) complex and imidazole in the presence of diethylazodicarboxylate and triphenylphosphine to provide azido tetrazoles CXXXVI.
It is noted that in some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
The compounds of this invention are useful for antagonizing tachykinins, in particular substance P and neurokinin A in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such treatment. This activity can be demonstrated by the following assays.
A. Receptor Expression in COS
To express the cloned human neurokinin-1 receptor (NK1R) transiently in COS, the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCl2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, New Haven, Conn.). The cells were incubated in 10% fetal calf serum, 2 mM glutamine, 100U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, N.Y.) in 5% CO2 at 37xc2x0 C. for three days before the binding assay.
B. Stable Expression in CHO
To establish a stable cell line expressing the cloned human NK1R, the cDNA was subcloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO media [10% fetal calf serum, 100 U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRH BIOSClENCES, Lenexa, Kans.), 0.7 mg/ml G418 (GIBCO)] in 5% CO2 at 37xc2x0 C. until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NK1R was selected for subsequent applications such as drug screening.
C. Assay Protocol using COS or CHO
The binding assay of human NK1R expressed in either COS or CHO cells is based on the use of 1251-substance P (1251-SP, from DU PONT, Boston, Mass.) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NK1R. Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, N.J.) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 125I-SP binding (approximately 50,000 to 200,000 cells). In the binding assay, 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 125I-Sp and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 4xc2x0 C. or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which was pre-wetted with 0.1% polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCl) three times and its radioactivity was determined by gamma counter.
The activation of phospholipase C by NK1R may also be measured in CHO cells expressing the human NK1R by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells are seeded in 12-well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of 3H-myoinositol by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 0.1 mM with or without the test compound, and incubation is continued at 37xc2x0 C. for 15 min. Substance P is added to the well at final concentration of 0.3 nM to activate the human NK1R. After 30 min of incubation at 37xc2x0 C., the media is removed and 0.1 N HCl is added. Each well is sonicated at 4xc2x0 C. and extracted with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1xc3x978 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0.1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acid and quantitated by beta counter.
In particular, the intrinsic tachykinin receptor antagonist activities of the compounds of the present invention may be demonstrated by this assay. The compounds of the following examples have activity in the aforementioned assay in the range of 0.05 nM to 10 xcexcM. The activity of the present compounds may also be demonstrated by the assay disclosed by Lei, et al., British J. Pharmacol., 105, 261-262 (1992).
With respect to the compounds disclosed in U.S. Pat. Nos. 5,387,595, 5,750,549 and Bioorg. and Med. Chem. Lett., 1345 (1995), the present compounds exhibit unexpected properties, such as with respect to duration of action and/or metabolism, such as enhanced oral bioavailability or absorption.
The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity. Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer""s disease, senile dementia, dementia of the Alzheimer""s type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson""s disease, Huntington""s disease, Pick""s disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson""s disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down""s syndrome; demyelinating diseases such as MS and ALS and other neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or cerebral oedema.
Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and bums; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn""s disease, irritable bowel syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere""s disease, surgery, migraine, variations in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia and incontinence; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud""s disease; and pain or nociception attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine.
The compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting.
The compounds of the present invention are particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of the present invention are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by other pharmacological agents, for example, rolipram.
Examples of such chemotherapeutic agents include alkylating agents, for example, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics.
Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla., USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 68(1), 163-172].
The compounds of the present invention are also of use in the treatment of emesis induced by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
It will be appreciated that the compounds of the present invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack.
A further aspect of the present invention comprises the compounds of the present invention in combination with a 5-HT3 antagonist, such as ondansetron, granisetron or tropisetron, or other anti-emetic medicaments, for example, a dopamine antagonist such as metoclopramide or domperidone or GABAB receptor agonists such as baclofen. Additionally, a compound of the present invention, either alone or in combination with one or more other anti-emetic therapeutic agents, may be administered in combination with an anti-inflammatory corticosteroid, such as dexamethasone, betamethasone, triamcinolone, triamcinolone acetonide, flunisolide, budesonide, or others such as those disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712. Dexamethasone (Decadron(trademark)) is particularly preferred. Furthermore, a compound of the present invention may be administered in combination with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor or cytotoxic antibiotic, as described above. In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
Suitable methods for determining the anti-emetic effects of compounds of the present invention are well known in the art, for example, using the ferret model of cisplatin-induced emesis described by F. D. Tattersall et al, in Eur. J. Pharmacol., (1993) 250, R5-R6.
The compounds of the present invention are also particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and headache, including migraine, acute or chronic tension headache, cluster headache, temporomandibular pain, and maxillary sinus pain.
The compounds of the present invention are also particularly useful in the treatment of depression including depressive disorders, for example, single episodic or recurrent major depressive disorders, and dysthymic disorders, depressive neurosis, and neurotic depression; melancholic depression including anorexia, weight loss, insomnia and early morning waking, and psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, anxiety and phobias; seasonal affective disorder; or bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder.
The present invention further provides a compound of the present invention for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of the present invention for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of the present invention or a composition comprising a compound of the present invention.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
The pharmaceutical compositions of this invention may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
The present invention is further directed to a method for the manufacture of a medicament for antagonizing the effect of substance P or another tachykinin at its receptor site or for the blockade of neurokinin-1 receptors or other tachykin receptors in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solution, suitably flavoured syrups, aqueous or oil suspensions, and emulsions with acceptable oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, or with a solubilizing or emulsifying agent suitable for intravenous use, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
For the treatment of the clinical conditions and diseases noted above, the compounds of this invention may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
According to a further aspect of the present invention, it may be desirable to treat any of the aforementioned conditions with a combination of a compound according to the present invention and one or more other pharmacologically active agents suitable for the treatment of the specific condition. The compound of the present invention and the other pharmacologically active agent(s) may be administered to a patient simultaneously, sequentially or in combination. For example, the present compound may employed directly in combination with the other active agent(s), or it may be administered prior, concurrent or subsequent to the administration of the other active agent(s). In general, the currently available dosage forms of the known therapeutic agents for use in such combinations will be suitable.
For example, a compound of the present invention may be presented together with another therapeutic agent as a combined preparation for simultaneous, separate, or sequential use for the relief of emesis. Such combined preparations may be, for example, in the form of a twin pack. A preferred combination comprises a compound of the present invention with a chemotherapeutic agent such as an alkylating agent, antimetabolite, mitotic inhibitor, or cytotoxic antibiotic, as described above.
Also, for the treatment of respiratory diseases, such as asthma, a compound of the present invention may be used in conjunction with a bronchodilator, such as a xcex22-adrenergic receptor agonist or a tachykinin antagonist which acts at neurokinin-2 receptors. Suitable xcex22-adrenergic receptor agonist include: Bambuterol (U.S. Pat. No. 4,419,364 issued to Draco on Dec. 6, 1983); Bitolterol mesylate (U.S. Pat. No. 4,138,581 issued to Sterling Feb. 6, 1979); Brosaterol (U.S. Pat. No. 4,276,299 issued to Zambon Jun. 30, 1981 and U.S. Pat. No. 4,520,200 issued to Zambon May 28, 1985); Carbuterol (U.S. Pat. No. 3,763,232 issued to Smith Kline Oct. 2, 1973); Clenbuterol (U.S. Pat. No. 3,536,712 issued to Boehringer Ingelheim Oct. 4, 1970); Cimaterol (U.S. Pat. No. 4,407,819 issued to American Cyanamid Oct. 4, 1983); Docarpamine (U.S. Pat. No. 4,228,183 issued to Tanabe Oct. 14, 1980); Dopexamine (U.S. Pat. No. 4,645,768 issued to Fisons Feb. 24, 1987); Formoterol (U.S. Pat. No. 3,994,974 issued to Yamanouchi Nov. 30, 1976); Mabuterol (U.S. Pat. No. 4,119,710 issued to Boehringer Ingelheim Oct. 10, 1978); Pirbuterol hydrochloride (U.S. Pat. No. 3,700,681 issued to Pfizer Oct. 24, 1972); Procaterol hydrochloride (U.S. Pat. No. 4,026,897 issued to Otsuka May 31, 1977); Ritodrine hydrochloride (U.S. Pat. No. 3,410,944 issued to North American Philips Nov. 12, 1968); or Salmeterol (U.S. Pat. No. 4,992,474 issued to Glaxo Feb. 21, 1991 and U.S. Pat. No. 5,091,422 issued to Glaxo Feb. 25, 1992).
Also, for the treatment of conditions that require antagonism of both neurokinin-1 and neurokinin-2, including disorders associated with bronchoconstriction and/or plasma extravasation in airways, such as asthma, chronic bronchitis, airways disease, or cystic fibrosis; neuropathy, such as diabetic or peripheral neuropathy and chemotherapy-induced neuropathy; osteoarthritis; rheumatoid arthritis; and migraine, a compound of the present invention may be used in conjunction with a tachykinin antagonist which acts at neurokinin-2 receptors, or with tachykinin receptor antagonist which acts at both neurokinin-1 and neurokinin-2 receptors.
Likewise, a compound of the present invention may be employed with a leucotriene antagonist, such a leucotriene D4 antagonist, exemplified by those disclosed in Patent Pub. EP O,480,717, published Apr. 15, 1992; Patent Pub. EP O 604,114, published June 1994; U.S. Pat. No. 5,270,324, issued Dec. 14, 1993; and U.S. Pat. No. 4,859,692, issued Aug. 22, 1989. This combination is particularly useful in the treatment of respiratory diseases such as asthma, chronic bronchitis and cough.
A compound of the present invention further may be used in conjunction with a corticosteroid such as Dexamethasone, Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712.
The present invention accordingly provides a method for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of the present invention and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of the present invention, a bronchodilator, and a pharmaceutically acceptable carrier.
Similarly, for the prevention or treatment of emesis a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, decadron, and zatisetron, or GABAB receptor agonists, such as baclofen. Likewise, for the prevention or treatment of migraine a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5HT1 agonists, especially sumatriptan.
It will be appreciated that for the treatment or prevention of migraine, a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5-HT1 agonists, especially sumatriptan, naratriptan, zolmatriptan or rizatriptan.
Likewise, for the treatment of behavioural hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine.
For the treatment or prevention of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an anti-inflammatory agent such as a bradykinin receptor antagonist.
The present invention also provides a composition comprising a compound of the present invention, a bronchodilator, and a pharmaceutically acceptable carrier.
It will be appreciated that for the treatment or prevention of pain or nociception or inflammatory diseases, a compound of the present invention may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, asprin, codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an analgesic, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an analgesic as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of pain or nociception.
Likewise, for the treatment of behavioral hyperalgesia, a compound of the present invention may be used in conjunction with an antagonist of N-methyl D-aspartate (NMDA), such as dizocilpine. For the prevention or treatment of inflammatory conditions in the lower urinary tract, especially cystitis, a compound of the present invention may be used in conjunction with an antiinflammatory agent, such as a bradykinin receptor antagonist.
It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents.
Suitable classes of anti-depressant agent include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, xcex1-adrenoreceptor antagonists and atypical anti-depressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable examples of tertiary amine tricyclics include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine, and pharmaceutically acceptable salts thereof. Suitable examples of secondary amine tricyclics include: amoxapine, desipramine, maprotiline, nortriptyline and protriptyline, and pharmaceutically acceptable salts thereof.
Suitable selective serotonin reuptake inhibitors include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
Suitable monoamine oxidase inhibitors include: isocarboxazid, phenelzine, tranylcypromine and selegiline, and pharmaceutically acceptable salts thereof.
Suitable reversible inhibitors of monoamine oxidase include: moclobemide, and pharmaceutically acceptable salts thereof.
Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include: venlafaxine, and pharmaceutically acceptable salts thereof.
Suitable CRF antagonists include those compounds described in International Patent Specification Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677.
Suitable atypical anti-depressants include: bupropion, lithium, nefazodone, trazodone and viloxazine, and pharmaceutically acceptable salts thereof.
Suitable classes of anti-anxiety agent include benzodiazepines and 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
Suitable benzodiazepines include: alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam, and pharmaceutically acceptable salts thereof.
Suitable 5-HT1A receptor agonists or antagonists include, in particular, the 5-HT1A receptor partial agonists buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.
Therefore, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anti-depressant or anti-anxiety agent, together with at least one pharmaceutically acceptable carrier or excipient.
In a further or alternative aspect of the present invention, there is provided a product comprising a compound of the present invention and an anti-depressant or anti-anxiety agent as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of depression and/or anxiety.
It will be appreciated that for the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present invention may be used in conjunction with other anorectic agents.
The present invention accordingly provides the use of a compound of the present invention and an anorectic agent for the manufacture of a medicament for the treatment or prevention of eating disorders.
The present invention also provides a method for the treatment or prevention of eating disorders, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an anorectic agent, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and an anorectic agent, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of the present invention and anorectic agent may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of eating disorders. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of the present invention and an anorectic agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of eating disorders.
Suitable anoretic agents of use in combination with a compound of the present invention include, but are not limited to, aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex, fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex and sibutramine; and pharmaceutically acceptable salts thereof.
A particularly suitable class of anorectic agent are the halogenated amphetamine derivatives, including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex and sibutramine; and pharmaceutically acceptble salts thereof.
Particularly preferred halogenated amphetamine derivatives of use in combination with a compound of the present invention include: fenfluramine and dexfenfluramine, and pharmaceutically acceptable salts thereof.
It will be appreciated that for the treatment or prevention of obesity, the compounds of the present invention may also be used in combination with a selective serotonin reuptake inhibitor (SSRI).
The present invention accordingly provides the use of a compound of the present invention and an SSRI for the manufacture of a medicament for the treatment or prevention of obesity.
The present invention also provides a method for the treatment or prevention of obesity, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of an SSRI, such that together they give effective relief.
In a further aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of obesity comprising a compound of the present invention and an SSRI, together with at least one pharmaceutically acceptable carrier or excipient.
It will be appreciated that the compound of the present invention and SSRI may be present as a combined preparation for simultaneous, separate or sequential use for the treatment or prevention of obesity. Such combined preparations may be, for example, in the form of a twin pack.
In a further or alternative aspect of the present invention, there is therefore provided a product comprising a compound of the present invention and an SSRI as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of obesity.
Suitable selective serotonin reuptake inhibitors of use in combination with a compound of the present invention include: fluoxetine, fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptable salts thereof.
As used herein xe2x80x9cobesityxe2x80x9d refers to a condition whereby a mammal has a Body Mass Index (BMI), which is calculated as weight per height squared (kg/m2), of at least 25.9. Conventionally, those persons with normal weight, have a BMI of 19.9 to less than 25.9.
The obesity herein may be due to any cause, whether genetic or environmental. Examples of disorders that may result in obesity or be the cause of obesity include overeating and bulimia, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich""s syndrome, Type II diabetes, GH-deficient subjects, normal variant short stature, Turner""s syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
xe2x80x9cTreatmentxe2x80x9d (of obesity) refers to reducing the BMI of the mammal to less than about 25.9, and maintaining that weight for at least 6 months. The treatment suitably results in a reduction in food or calorie intake by the mammal.
xe2x80x9cPreventionxe2x80x9d(of obesity) refers to preventing obesity from occurring if the treatment is administered prior to the onset of the obese condition. Moreover, if treatment is commenced in already obese subjects, such treatment is expected to prevent, or to prevent the progression of, the medical sequelae of obesity, such as, e.g., arteriosclerosis, Type II diabetes, polycystic ovarian disease, cardiovascular diseases, osteoarthritis, dermatological disorders, hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia, and cholelithiasis.
A further aspect of the present invention comprises the use of a compound of the present invention for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of the present invention for blocking the phase-shifting effects of light in a mammal.
The present invention further relates to the use of a compound of the present invention for enhancing or improving sleep quality, in particular by increasing sleep efficiency and augmenting sleep maintenance, as well as for preventing and treating sleep disorders and sleep disturbances, in a mammal.
In a preferred embodiment, the present invention provides a method for the phase advance or phase delay in the circadian rhythm of a subject which comprises administering to the subject an appropriate amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
The present invention is further directed to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) (xe2x80x9cDIMSxe2x80x9d) which can arise from psychophysiological causes, as a consequence of psychiatric disorders (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing.
As used herein the term xe2x80x9cmammalsxe2x80x9d includes animals of economic importance such as bovine, ovine, and porcine animals, especially those that produce meat, as well as domestic animals, sports animals, zoo animals, and humans, the latter being preferred.
It will be appreciated that when using any combination described herein, both the compound of the present invention and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term xe2x80x9ccombinationxe2x80x9d also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a xe2x80x9cfast dissolving oral formulationxe2x80x9d is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds.
By xe2x80x9creasonable period of timexe2x80x9d is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament.
The compounds of this invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician.
In the treatment of the conditions associated with an excess of achykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular bout 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention.